Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria ...from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration.
Mitochondrial trafficking in neurons Schwarz, Thomas L
Cold Spring Harbor perspectives in biology,
2013-Jun-01, 2013-06-01, 20130601, Letnik:
5, Številka:
6
Journal Article
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Neurons, perhaps more than any other cell type, depend on mitochondrial trafficking for their survival. Recent studies have elucidated a motor/adaptor complex on the mitochondrial surface that is ...shared between neurons and other animal cells. In addition to kinesin and dynein, this complex contains the proteins Miro (also called RhoT1/2) and milton (also called TRAK1/2) and is responsible for much, although not necessarily all, mitochondrial movement. Elucidation of the complex has permitted inroads for understanding how this movement is regulated by a variety of intracellular signals, although many mysteries remain. Regulating mitochondrial movement can match energy demand to energy supply throughout the extraordinary architecture of these cells and can control the clearance and replenishing of mitochondria in the periphery. Because the extended axons of neurons contain uniformly polarized microtubules, they have been useful for studying mitochondrial motility in conjunction with biochemical assays in many cell types.
Mitochondria are mobile organelles and cells regulate mitochondrial movement in order to meet the changing energy needs of each cellular region. Ca(2+) signaling, which halts both anterograde and ...retrograde mitochondrial motion, serves as one regulatory input. Anterograde mitochondrial movement is generated by kinesin-1, which interacts with the mitochondrial protein Miro through an adaptor protein, milton. We show that kinesin is present on all axonal mitochondria, including those that are stationary or moving retrograde. We also show that the EF-hand motifs of Miro mediate Ca(2+)-dependent arrest of mitochondria and elucidate the regulatory mechanism. Rather than dissociating kinesin-1 from mitochondria, Ca(2+)-binding permits Miro to interact directly with the motor domain of kinesin-1, preventing motor/microtubule interactions. Thus, kinesin-1 switches from an active state in which it is bound to Miro only via milton, to an inactive state in which direct binding to Miro prevents its interaction with microtubules. Disrupting Ca(2+)-dependent regulation diminishes neuronal resistance to excitotoxicity.
Cells keep their energy balance and avoid oxidative stress by regulating mitochondrial movement, distribution, and clearance. We report here that two Parkinson's disease proteins, the Ser/Thr kinase ...PINK1 and ubiquitin ligase Parkin, participate in this regulation by arresting mitochondrial movement. PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. Removal of Miro from the mitochondrion also detaches kinesin from its surface. By preventing mitochondrial movement, the PINK1/Parkin pathway may quarantine damaged mitochondria prior to their clearance. PINK1 has been shown to act upstream of Parkin, but the mechanism corresponding to this relationship has not been known. We propose that PINK1 phosphorylation of substrates triggers the subsequent action of Parkin and the proteasome.
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► PINK1 or Parkin expression arrests the movement of neuronal mitochondria ► PINK1 and Parkin associate with the motor/adaptor Miro on depolarized mitochondria ► PINK1 phosphorylates Miro and causes it to be degraded by the proteasome ► PINK1 requires Parkin to cause Miro degradation
Two proteins implicated in Parkinson's disease function to quarantine damaged mitochondria. They sever ties to the microtubule network by triggering degradation of the kinesin adaptor Miro.
To minimize oxidative damage to the cell, malfunctioning mitochondria need to be removed by mitophagy. In neuronal axons, mitochondrial damage may occur in distal regions, far from the soma where ...most lysosomal degradation is thought to occur. In this paper, we report that PINK1 and Parkin, two Parkinson's disease-associated proteins, mediate local mitophagy of dysfunctional mitochondria in neuronal axons. To reduce cytotoxicity and mimic physiological levels of mitochondrial damage, we selectively damaged a subset of mitochondria in hippocampal axons. Parkin was rapidly recruited to damaged mitochondria in axons followed by formation of LC3-positive autophagosomes and LAMP1-positive lysosomes. In PINK1(-/-) axons, damaged mitochondria did not accumulate Parkin and failed to be engulfed in autophagosomes. Similarly, initiation of mitophagy was blocked in Parkin(-/-) axons. Our findings demonstrate that the PINK1-Parkin-mediated pathway is required for local mitophagy in distal axons in response to focal damage. Local mitophagy likely provides rapid neuroprotection against oxidative stress without a requirement for retrograde transport to the soma.
Résumé
En l’absence d’extension à distance, la prise en charge thérapeutique de l’adénocarcinome du pancréas (AP) dépend du degré d’envahissement locorégional. Bien que longtemps hétérogènes, les ...classifications de ce type de tumeurs tendent à s’homogénéiser (MD Anderson Cancer Center MDACC, National Comprehensive Cancer Network NCCN). Selon le degré d’envahissement des vaisseaux mésentériques, en particulier, l’AP sera décrit comme résécable d’emblée,
borderline
(BR) ou localement avancé non résécable (LANR) sur des critères radiologiques précis et objectifs. Cette classification n’est possible de manière reproductible que depuis la standardisation des protocoles et des comptes rendus d’examens radiologiques performants. Enfin, grâce à cette standardisation, la prise en charge thérapeutique peut être harmonisée et optimisée.
Cells allocate substantial resources toward monitoring levels of nutrients that can be used for ATP generation by mitochondria. Among the many specialized cell types, neurons are particularly ...dependent on mitochondria due to their complex morphology and regional energy needs. Here, we report a molecular mechanism by which nutrient availability in the form of extracellular glucose and the enzyme O-GlcNAc Transferase (OGT), whose activity depends on glucose availability, regulates mitochondrial motility in neurons. Activation of OGT diminishes mitochondrial motility. We establish the mitochondrial motor-adaptor protein Milton as a required substrate for OGT to arrest mitochondrial motility by mapping and mutating the key O-GlcNAcylated serine residues. We find that the GlcNAcylation state of Milton is altered by extracellular glucose and that OGT alters mitochondrial motility in vivo. Our findings suggest that, by dynamically regulating Milton GlcNAcylation, OGT tailors mitochondrial dynamics in neurons based on nutrient availability.
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•Increasing extracellular glucose selectively decreases mitochondrial movement•Milton O-GlcNAcylation by OGT modulates mitochondrial motility•Milton O-GlcNAcylation mediates the effect of extracellular glucose.•OGT, by responding to altered nutrient states, can regulate mitochondrial dynamics
The regulatory addition of O-GlcNAc to a protein involved in mitochondrial transport links mitochondrial dynamics to glucose availability, suggesting a means to coordinate the distribution of energy production within cells according to need.
Recent findings of new Higgs modes in unconventional superconductors require a classification and characterization of the modes allowed by nontrivial gap symmetry. Here we develop a theory for a ...tailored nonequilibrium quantum quench to excite all possible oscillation symmetries of a superconducting condensate. We show that both a finite momentum transfer and quench symmetry allow for an identification of the resulting Higgs oscillations. These serve as a fingerprint for the ground state gap symmetry. We provide a classification scheme of these oscillations and the quench symmetry based on group theory for the underlying lattice point group. For characterization, analytic calculations as well as full scale numeric simulations of the transient optical response resulting from an excitation by a realistic laser pulse are performed. Our classification of Higgs oscillations allows us to distinguish between different symmetries of the superconducting condensate.
Importance of a species’ socioecology Marshall-Pescini, Sarah; Schwarz, Jonas F. L.; Kostelnik, Inga ...
Proceedings of the National Academy of Sciences,
10/2017, Letnik:
114, Številka:
44
Journal Article
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A number of domestication hypotheses suggest that dogs have acquired a more tolerant temperament than wolves, promoting cooperative interactions with humans and conspecifics. This selection process ...has been proposed to resemble the one responsible for our own greater cooperative inclinations in comparison with our closest living relatives. However, the socioecology of wolves and dogs, with the former relying more heavily on cooperative activities, predicts that at least with conspecifics, wolves should cooperate better than dogs. Here we tested similarly raised wolves and dogs in a cooperative string-pulling task with conspecifics and found that wolves outperformed dogs, despite comparable levels of interest in the task. Whereas wolves coordinated their actions so as to simultaneously pull the rope ends, leading to success, dogs pulled the ropes in alternate moments, thereby never succeeding. Indeed in dog dyads it was also less likely that both members simultaneously engaged in other manipulative behaviors on the apparatus. Different conflict-management strategies are likely responsible for these results, with dogs’ avoidance of potential competition over the apparatus constraining their capacity to coordinate actions. Wolves, in contrast, did not hesitate to manipulate the ropes simultaneously, and once cooperation was initiated, rapidly learned to coordinate in more complex conditions as well. Social dynamics (rank and affiliation) played a key role in success rates. Results call those domestication hypotheses that suggest dogs evolved greater cooperative inclinations into question, and rather support the idea that dogs’ and wolves’ different social ecologies played a role in affecting their capacity for conspecific cooperation and communication.
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